Percutaneous absorption composition

ABSTRACT

The embodiments provide a percutaneous absorption composition for a basic medicament having improved transdermal absorbability. The percutaneous absorption composition comprises a sorbic acid and/or a metal sorbate as a percutaneous absorption promotor. The molar ration of the sorbic acid and/or the metal sorbate to the basic medicament is 0.5-2.5. The composition of the present disclosure may further comprise a basic component.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all applications for which a foreign or domestic priority claimis identified in the Application Data Sheet as filed with the presentapplication are hereby incorporated by reference under 37 CFR 1.57.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to an external preparation containing abasic medicament. Specifically, the present invention relates to acomposition containing sorbic acid as a transdermal absorptionaccelerator.

Description of the Related Art

Several techniques for improving percutaneous absorption of a basicmedicament are known. For example, the lipid solubility of a basicmedicament may be adjusted by forming an equimolar salt of the basicmedicament and an organic acid (Patent Document 1). An ionic liquidconsisting of an aliphatic acid and an organic amine compound has alsobeen used as a transdermal absorption accelerator (Patent Document 2).However for some medicaments, better absorbability was still required ora long-term stable formulation couldn't be obtained with conventionaltechnique.

Sorbic acid is known as an antiseptic gent, and can be utilized for awater-based adhesive patch such as cataplasms (Patent Document 3).However, it has not been known that sorbic acid can exhibit an excellenttransdermal absorbability accelerating effect for the basic medicament.Neither using them as a transdermal absorption accelerator nor anon-aqueous absorption composition has been known.

PRIOR ART DOCUMENTS Patent Documents

Patent Document 1: W02010/016219

Patent Document 2: W02009/066457

Patent Document 3: JP2014-125483A

SUMMARY OF THE INVENTION Problem to be Solved

An object of the present invention is to provide a percutaneousabsorption composition which exhibits an excellent percutaneousabsorbability of a basic medicament and a percutaneous absorptionpromoter for the basic medicament.

As a result of intensive investigation, the present inventors has foundthat sorbic acid exhibits an excellent accelerating effect forpercutaneous absorption of basic medicament, and the effect can befurther increased by using sorbic acid in combination with a basiccomponent.

The present invention provides the following (1) to (5);

-   -   (1) A percutaneous absorption composition comprising a basic        medicament or a salt thereof and sorbic acid and/or its metal        salt.    -   (2) The percutaneous absorption composition described in above        (1), wherein a concentration of the sorbate component is 0.5-2.5        mol with respect to 1 mol of the basic medicament.    -   (3) The percutaneous absorption composition described in        above (1) or (2), further comprising an organic basic compound        and/or an inorganic basic component.    -   (4) The percutaneous absorption composition described in above        (3), wherein the concentration of the organic basic compound        and/or inorganic basic component is 0.4-3.0 mol with respect to        1 mol of the sorbate component.    -   (5) A percutaneous absorption promoter for a basic medicament        comprising sorbic acid and/or its metal salt, and an organic        basic compound and or an inorganic basic component.

Effect of the Invention

According to the present invention, a percutaneous absorptioncomposition which exhibits an excellent transdermal permeability ofbasic medicament and a percutaneous absorption promoter for basicmedicament with excellent transdermal absorption accelerating effect areprovided.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Certain embodiments provide a percutaneous absorption compositioncomprising an basic medicament or a salt thereof, and a sorbatecomponent. The sorbate component may include a sorbic acid and/or metalsorbate. In some embodiments, the percutaneous absorption promoter for abasic medicament of the present disclosure comprises a sorbatecomponent. In some embodiments, the percutaneous absorption promoter mayfurther comprise a basic component.

Basic Medicament

In some embodiments, a basic medicament has a basic functional group,such as an amino group. Specifically, a hypnotic/sedative agent such asflurazepam, rilmazafone, medetomidine, dexmedetomidine; astimulant/antihypnotic agent such as methamphetamine, methylphenidate; apsychoneurotic agent such as imipramine, diazepam, sertraline,fluvoxamine, paroxetine, citalopram, fluoxetine, alprazolam,haloperidol, clomipramine, amitriptyline, desipramine, amoxapine,maprotiline, mirtazapine, setiptiline, duloxetine, diazepam, etizolam; atopical anesthesia such as lidocaine, procaine, tetracaine, dibucaine;an agent for urinary such as oxybutynin, tamsulosin, propiverine,imidafenacin, solifenacin, darifenacin, tolterodine, an muscle relaxantsuxametonium such as tizanidine, eperisone, pridinol, suxamethonium; anagent for genital organs such as ritodrine, meluadrine; anantiparkinsonian agent such as pergolide, bromocriptine,trihexyphenidyl, amantadine, ropinirole, talipexole, pramipexole,rotigotine, cabergoline, Selegiline, rasagiline; an anti-migraine agentsuch as dihydroergotamine, sumatriptan, ergotamine, flunarizine,cyproheptadine; an antihistamine agent such as clemastine,diphenhydramine, chlorpheniramine, diphenylpyraline; a bronchodilatoragent such as tulobuterol, procaterol, salbutamol, clenbuterol,fenoterol, terbutaline, isoprenaline, a cardiotonic agent such asdenopamine, a peripheral vasodilators such as nicametate, tolazoline; asmoking-cessation aid such as nicotine, varenicline; a cardiovascularpreparation such as atenolol, bisoprolol, metoprolol, carvedilol,carteolol, valsartan, clonidine; an antiarrhythmic agent such aspropranolol, alprenolol, procainamide, mexiletine; prophylactic agentfor digestive ulcer such as proglumide, cetraxate, spizofurone,cimetidine; a gastrointestinal motility improving agent such asdomperidone, cisapride; an anti-allergy agent such as ketotifen,azelastine, emedastine; an antiviral agent such as acyclovir; analzheimer's disease treating e agent such as donepezil, tacrine,arecoline, galantamine, rivastigmine; an serotonin receptorantagonist/antiemetic agent such as ondansetron, granisetron,ramosetron, azasetron; an opioid analgesic such as morphine, codeine,fentanyl, oxycodone, hydromorphone; an antifungal agent such asterbinafine, butenafine, amorolfine, neticonazole, miconazole,luliconazole, itraconazole can be exemplified.

The basic medicament is preferably used in a state of itspharmaceutically acceptable acid addition salt due to its stability andlow dermal irritancy, though it can also be utilized in its free state.Examples of the acid addition salt include an inorganic salt such ashydrochloride salt, sulfate salt, and hydrobromate; and an organic saltsuch as fumarate, maleate, citrate, and tartrate.

The basic medicament can be used alone or in combination with one ormore other basic medicament. In some embodiments, the basic medicamentmay be selected from the group consisting of tizanidine hydrochloride,oxycodone hydrochloride, lidocaine hydrochloride, and a combinationthereof. In some embodiments, the basic medicament may comprise at leastone compound selected from tizanidine hydrochloride, and oxycodonehydrochloride.

Sorbate Component

Sorbic acid accelerates percutaneous absorption of basic medicament.Without being bound to the theory, sorbic acid may bind ionically to thebasic medicament to form an ionic liquid in the composition. In someembodiments, the ionic liquid may be tizanidine sorbate, oxycodonesorbate or lidocaine sorbate. Both the free sorbic acid and a metal saltof sorbic acid such as sodium sorbate, potassium sorbate, and calciumsorbate, can be used. In some embodiments, the free sorbic acid and ametal salt of sorbic acid can also be used in combination. When thesorbic acid and metal salt of sorbic acid are used in combination, theterm “sorbate component” also refers to sorbic acid and metal salt ofsorbic acid collectively. In this case, the term “concentration ofsorbate component” as used in this application denotes total amount ofthe sorbic acid and the metal salt of sorbic acid together. In caseswhere either sorbic acid or metal salt of sorbic acid is used alone, theterm “concentration of sorbate component” denotes the amount of thesorbic acid or the metal salt of sorbic acid.

The concentration of sorbate component can be selected from the rangeof, for example about 0.1 to about 3.0 mol, about 0.5 to about 2.5 mol,and about 0.9 to about 2.1 mol per 1 mol of the basic medicament. Insome embodiments, the percutaneous absorption accelerating effect isremarkable when the concentration of the sorbate component is betweenabout 0.5 mol and about 2.5 mol. However, the concentration of over 3mol may sometimes reduce the permeability of medicament.

Basic Component

In some embodiments, the composition of the present disclosure mayfurther comprise a basic component. The basic component may include oneor more of organic basic compound, inorganic basic compound, and salt ofa strong base. By using the basic component in combination withabove-mentioned sorbate component, percutaneous absorbability of thebasic medicament can be further improved. Thus, the combination of thebasic component and the sorbate component can thus be utilized as anexcellent transdermal absorption accelerator.

In some embodiments, the organic basic compound may be a C₂₋₉alkanolamine such as monoethanolamine, monoisopropanolamine,diethanolamine, diisopropanolamine, triethanolamine,triisopropanolamine, ethylenediamine, and trishydroxymethylaminomethane(trometamol), or a basic amino acid such as arginine. In someembodiments, the organic basic compound is an organic amine compoundhaving three hydroxyl groups in a molecule, such as triethanolamine,triisopropanolamine, or trishydroxymethylaminomethane. In someembodiments, the organic basic compound is triethanolamine. Thecomposition may comprise one or more organic basic compounds.

In some embodiments, the inorganic basic compound is a compoundcontaining an alkali metal or an alkali earth metal. Examples ofinorganic basic compound include hydroxide such as sodium hydroxide,potassium hydroxide, calcium hydroxide. In some embodiments, the salt ofa strong base includes a metal salt of carboxylic acid such as sodiumbenzoate, sodium propionate, calcium propionate, sodium fumarate, sodiumsorbate, and potassium sorbate; a metal salt of hydroxyl acid such assodium lactate, sodium tartrate, potassium tartrate, and sodium citrate;sodium sulfite; and sodium pyrosulfite. In some embodiments, when themetal salt of sorbic acid, such as potassium sorbate, is used as the“sorbate component,” it may be classified not only as a “sorbatecomponent,” but also as a “basic component”. Thus, when calculating theamount for each component, the amount of metal salt of sorbic acidshould be counted both as a part of the “sorbate component” and a partof the “basic component”.

In some embodiments, when a hydrochloride of a basic medicament ispresent as an active ingredient, and a basic component is also presentin the composition, the metallic ions which constitutes the inorganicbasic compound and/or the salt of a strong base can behave as a“hydrochloric acid scavenger” as well. The metallic ion scavengeshydrochloric acid attached to the basic medicament to formhydrochloride, thus generates the free form of the basic medicament andimproves the skin permeability of the medicament.

The amount of the basic component can be within the range of about 0.4mol to about 3.0 mol, about 0.5 mol to about 2.5mol, about 0.5 mol toabout 2.0 mol, or about 0.5 mol to about 1.6 mol per 1 mol of sorbatecomponent.

Other Percutaneous Absorption Accelerator

In some embodiments, the composition of the present disclosure mayfurther include one or more compound that can dissolve the medicamentand sorbic acid, and having percutaneous absorption accelerating effecton the medicament. For examples, percutaneous absorption acceleratorsuch as aliphatic acid, alcohol, ester compound, and amide compound maybe useful. The composition of the present invention is a non-aqueouscomposition which does not substantially contain water. For example, thenon-aqueous composition contains less than about 3.0%, or less thanabout 1.0% water.

As used herein, the aliphatic acid as a percutaneous absorptionaccelerator may include one or more C₄₋₂₀ saturated or unsaturatedaliphatic acid, excluding sorbic acid. Examples of the aliphatic acidinclude levulinic acid, capric acid, lauric acid, myristic acid,palmitic acid, stearic acid, isostearic acid, and oleic acid. In someembodiments, the composition further contains at least one unsaturatedaliphatic acid. In some embodiments, the unsaturated aliphatic acid isoleic acid. When the aliphatic acid is present in the composition, thetotal concentration of sorbate component and the aliphatic acid is about0.8 mol to about 2.5 mol, or about 0.8 mol to about 2.0 mol per 1 mol ofthe basic component. In some embodiment, the total weight of the sorbatecomponent and the aliphatic acid may be about 2.0% to about 3.0% byweight, or about 2.0% to about 2.5% by weight of the total weight of theadhesive layer.

In some embodiments, the composition may further contain an alcohol. Thealcohol may be monovalent alcohol such as lauryl alcohol, myristylalcohol, oleyl alcohol, isostearyl alcohol, and cetyl alcohol; divalentalcohol such as propylene glycol, butylene glycol, dipropylene glycol,diisobutylene glycol, polyethylene glycol, and hexylene glycol; ortrivalent alcohol such as glycerin, and hexanetriol. In someembodiments, the composition may include two or more alcohols. In someembodiments, the composition contains oleyl alcohol.

In some embodiments, the composition may also contain an ester compound.The ester compound may be diethyl sebacate, methyl laurate, diisopropyladipate, isopropyl myristate, or medium-chain triglyceride. Medium-chaintriglyceride may include triglycerides whose fatty acids have C₆₋₁₂aliphatic chain. In some embodiments, the composition may furthercontain an amide compound, such as lauric acid diethanolamide.

In some embodiments, the composition can be provided as a homogeneoussolution prepared by mixing the basic medicament and/or salt thereof,sorbate component, and the basic component with a solvent. In someembodiments, the composition further comprises an aliphatic acid, analcohol, and/or an ester compound.

Matrix Type Plaster

A matrix type plaster can be obtained from the composition of thepresent composition by dispersing above mentioned solution in anadhesive layer comprising an appropriate polymer. The useful polymer mayinclude acrylic polymer, rubber polymer, silicone polymer, or vinylether-based polymer. In some embodiments, a rubber polymer such asstyrene-isoprene-styrene block copolymer, styrene-butadiene-styreneblock copolymer, polyisoprene, polyisobutylene, and/or polybutadiene canbe utilized. The concentration of the rubber polymer may be about 5% toabout 40% by weight, or about 10% to about 30% by weight, or about 5% toabout 25% of the total weight of the dried adhesive layer. Theconcentration of the acrylic polymer or silicone polymer may be about45% to about 95% by weight, or about 50% to about 90% by weight of thetotal weight of the dried adhesive layer.

In some embodiments, the adhesive layer further contains a filler. Thefiller can improve not only the adhesion of the adhesive layer, but alsothe drug release rate. The concentration of the filler can be about 0.5%to about 5% by weight of the total weight of the adhesive layer. Thefiller may be selected from hydrous silica, fumed silica, talc,crystalline cellulose, starch, carmellose, and metal salt of carmellose.In some embodiments, the filler may be the fumed silica. A commerciallyavailable fumed silica, AEROSIL®, is an example.

The adhesive layer may further contain other additives such as tackifierresin, softener, and/or antioxidant. Examples of a tackifier resininclude rosin ester, hydrogenated rosin ester, rosin maleate, alicyclicsaturated hydrocarbon resin, terpene resin, and polyolefin resin.Examples of the softener include naphthenic processing oil; vegetableoil such as camellia oil, castor oil; liquid rubber such as liquidpolybutene, liquid isoprene robber; and liquid paraffin. Examples of theantioxidant include butyl hydroxyl toluene, ascorbic acid, propylgallate, sodium sulfite, and sodium pyrosulfite.

When the matrix type plaster is prepared from the composition disclosedherein, the concentration of the basic medicament can be about 0.5% toabout 10% by weight, or about 1% to about 5% by weight of the totalamount of the dried adhesive layer. Additionally, in some embodiments,at least two of monovalent alcohol such as oleyl alcohol, divalentalcohol such as butylene glycol, propylene glycol, and trivalent alcoholsuch as glycerin are used in combination. In some embodiments, theconcentration of the alcohols can be about 15% to about 35% by weight,about 20% to about 30% by weight, or about 22% to about 28% by weight ofthe dried adhesive layer.

EXAMPLES

Hereinafter, the present disclosure is explained in detail withexamples. The present disclosure is not limited in any way by theseexamples.

Example 1 Preparing an Adhesive Patch Containing Tizanidine and SorbicAcid

Tizanidine hydrochloride, sorbic acid, sodium lactate, sodium benzoate,triethanolamine, diethyl sebacate, isopropyl myristate, glycerin,DiPG(dipropylene glycol), oleyl alcohol, propyl gallate, and liquidparaffin are mixed, then heated (60° C.) and dissolved to yield ahomogeneous solution. Terpene resin dissolved in toluene,styrene-isoprene-styrene block copolymer(SIS5002) dissolved in toluene,and fumed silica were added to the solution and uniformly mixed to yieldan adhesive composition containing the active ingredient. The obtainedadhesive composition containing the active ingredient are coated ontothe PET film. Then, it was dried for 10 minutes at 80° C. to eliminatetoluene. Thus adhesive patch containing tizanidine and sorbic acid wasprepared. Amount(weight %) of each component is as shown in table 1.

Comparative Example 1 Preparing an Adhesive Patch Containing Tizanidine

Adhesive patches containing the composition(weight %) shown in Table 1was prepared by using the similar procedure as described in Example 1.

Example 2 and Comparative Example 2 Preparing Adhesive PatchesContaining Oxycodone

Adhesive patches containing oxycodone as the composition(weight %) shownin Table 1 was prepared by using the similar procedure as described inExample 1.

In Vitro Transdermal Permeation Study

Transdermal permeation of medicament was evaluated with the use of Franzcell for each adhesive patches prepared in Examples and ComparativeExamples. Cumulative skin permeation amount at each sampling points areshown in Table 1. Hairless rat abdominal skin was used for the adhesivepatches containing tizanidine prepared in Example 1 and ComparativeExample 1, pig skin was used for the adhesive patches containingoxycodone prepared in Example 2 and Comparative Example 2.

TABLE 1 Ex. Com. Com. Com. Com. Ex. Ex. Com. Com. 1-1 1-1 1-2 1-3 1-42-1 2-2 2-1 2-2 Q907 Q914 Q910 Q137 Q891 M304 M305 M300 M292 TizanidineHydrochloride 1.72 1.72 1.72 1.72 1.72 Oxycodone Hydrochloride 3.4613.461 3.461 3.461 Sorbic Acid 1.33 0.70 1.30 Potassium sorbate 1.30Levulinic acid 0.69 1.38 1.00 Isostearic acid 3.00 Oleic acid 4.00 1.003.00 3.00 4.00 4.00 Sodium lactate 0.73 0.73 0.73 0.73 0.73 Sodiumbenzoate 0.2 0.2 0.2 0.2 0.2 Potassium hydroxide 0.55 Triethanolamine2.00 1.00 0.50 0.50 0.50 Diisopropanolamine 1.50 1.50 1.50 1.50 Diethylsebacate 5.00 5.00 5.00 5.00 5.00 Isopropyl myristate 5.00 5.00 5.005.00 5.00 Medium-chain triglyceride 10.00 10.00 10.00 10.00 Propylenecarbonate 5.00 5.00 5.00 3.00 Glycerin 5.00 5.00 5.00 10.00 5.00 4.004.00 3.00 5.00 propylene glycol 4.00 4.00 4.00 Butylene glycol 3.00 3.003.00 Oleyl alcohol 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 3.00PEG200 7.00 Benzyl alcohol 4.00 Sodium pyrosulfite 0.10 0.10 0.10 0.100.10 0.10 0.10 0.10 0.10 Propyl gallate 0.05 0.05 0.05 0.05 0.05 0.050.05 0.05 0.05 AEROSIL ® 3 3 3 3 3 3 3 3 3 Liquid paraffin 10.87 12.5112.32 11.7 12.7 16.91 17.61 17.34 17.89 Terpene resin 32 32 32 32 32 2626 26 27 SIS5002 16 16 16 16 16 15 15 15 15 Total 100 100 100 100 100100 100.02 100 100 (base)/(sorbic acid) 1.84 1.37 1.02 (sorbicacid)/(API) 2.00 1.75 1.36 (aliphatic acid)/(base) 0.54 0.39 1.01 1.201.20 1.25 1.88 1.05 1.20 Cumulative skin 2 hr 21.3 6.5 1.8 3.6 3.8 0.8810.675 0.235 permeation 4 hr 80.7 28.2 10.4 11.9 15.5 10.39 11.23 0.4918.577 amount 6 hr 135.3 49.8 24.9 24.4 30.6 (μg/cm²) 8 hr 172.3 71.540.1 39.8 46.7 36.12 73.08 4.059 44.9 10 hr  192.8 87.9 55.8 56.9 62.424 hr  348.5 318.2 40.22 197.2

The adhesive patch of Example 1-1 containing sorbic acid exhibitedhigher transdermal permeability relative to that of Comparative Example1-1 to 1-4 containing higher fatty acid instead of sorbic acid. Adhesivepatches of Example 2 and Comparable Example 2 containing oxycodoneinstead of tizanidine also showed similar results as those containingtizanidine. That is, adhesive patches of present invention containingsorbic acid (Examples 2-1 and 2-2) exhibited higher skin permeabilityrelative to adhesive patches

Example 3 Investigation of the Optimum Amount of Sorbic Acid and BasicComponent

Adhesive patches as the composition (weight %) shown in Table 2 wereprepared. In vitro transdermal permeability test with use of rat skinwas conducted for the obtained patches. The results are shown in Table2.

TABLE 2 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. 3-1 3-2 3-3 3-4 3-5 3-6 3-73-8 3-9 Q909 Q907 Q906 Q900 Q899 Q898 Q901 Q897 Q905 TizanidineHydrochloride 1.72 1.72 1.72 1.72 1.72 1.72 1.72 1.72 1.72 Sorbic Acid0.66 0.33 0.33 0.33 0.33 0.33 2.65 2.65 3.32 Sodium lactate 0.73 0.730.73 0.73 0.73 0.73 0.73 0.73 0.73 Sodium benzoate 0.20 0.20 0.20 0.200.20 0.20 0.20 0.20 0.20 Triethanolamine 1.50 2.00 1.50 1.00 0.50 0.001.00 0.50 0.00 Diethyl sebacate 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.005.00 Isopropyl myristate 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00Glycerin 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 propylene glycol4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00 Butylene glycol 3.00 3.003.00 3.00 3.00 3.00 3.00 3.00 3.00 Oleyl alcohol 10.00 10.00 10.00 10.0010.00 10.00 10.00 10.00 10.00 AEROSIL ® 3 3 3 3 3 3 3 3 3 Sodiumpyrosulfite 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 0.10 Propyl gallate0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 0.05 Liquid paraffin 12.04 10.8711.37 11.87 12.37 12.87 10.55 11.05 10.88 Terpene resin 32.00 32.0032.00 32.00 32.00 32.00 32.00 32.00 32.00 SIS5002 16.00 16.00 16.0016.00 16.00 16.00 16.00 16.00 16.00 Total 100 100 100 100 100 100 100100 100 (base)/(sorbic acid) 3.05 1.08 1.51 1.23 0.95 0.67 0.62 0.480.27 (sorbic acid)/(API) 0.99 2.00 2.00 2.00 2.00 2.00 3.99 3.99 5.00Cumulative skin 2 hr 10.08 21.30 4.40 14.70 5.80 4.7 3.40 3.10 3.50permeation 4 hr 35.20 80.70 29.40 53.80 33.70 28.9 25.60 24.00 20.80amount 6 hr 54.00 135.30 63.70 91.30 66.50 57.6 48.20 47.50 45.40(μg/cm²) 8 hr 66.70 172.30 93.00 119.30 99.40 85.7 71.90 72.50 66.90 10hr  77.30 192.80 115.20 137.70 123.60 107.5 87.30 93.50 82.80

Adhesive patch of Example 3-1 exhibited slightly less transdermalpermeability because the ratio of sorbic acid to basic component issmall, though all adhesive patches of Examples from 3-1 to 3-9containing sorbic acid exhibited excellent skin permeability. Adhesivepatches of Example 3-7 to 3-9 contain excessive amounts of sorbic acidrelative to tizanidine, and also exhibited slightly less transdermalpermeability.

Investigation of Optimum Basic Component

Adhesive patches containing sorbic acid and a variety of basic componentas the composition(weight %) shown in Table 3 were prepared. In vitrotransdermal permeability test with use of rat skin was conducted for theobtained patches. The results are shown in Table 3.

TABLE 3 Ex. Ex. Ex. Ex. Ex. Ex. Ex. Ex. 4-1 4-2 4-3 4-4 4-5 4-6 4-7 4-8Q916 Q949 Q950 Q162 Q161 Q163 Q899 Q946 Tizanidine Hydrochloride 1.721.72 1.72 1.72 1.72 1.72 1.72 1.72 Sorbic Acid 1.33 1.33 1.33 1.33 1.331.33 1.33 0.66 Potassium sorbate 0.89 Sodium lactate 0.73 0.73 Sodiumbenzoate 0.20 0.20 Sodium hydroxide 0.24 0.24 0.24 0.24 0.24Triethanolamine 0.50 0.25 0.50 1.00 0.50 0.50 Arginine 1.03 Trometamol0.72 0.72 Diethyl sebacate 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00Isopropyl myristate 5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 Glycerin5.00 5.00 5.00 5.00 5.00 5.00 5.00 5.00 propylene glycol 4.00 4.00 4.004.00 Butylene glycol 3.00 3.00 3.00 4.00 4.00 4.00 3.00 4.00 Oleylalcohol 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 AEROSIL ® 3.003.00 3.00 3.00 3.00 3.00 3.00 3.00 Sodium pyrosulfite 0.10 0.20 0.200.10 0.20 0.10 0.10 0.10 Propyl gallate 0.05 0.05 0.05 0.05 0.05 0.050.05 0.05 Liquid paraffin 11.65 13.08 12.77 11.31 11.06 10.56 10.3711.08 Terpene resin 32.00 32.00 32.00 32.00 32.00 32.00 32.00 32.00SIS5002 16.00 16.00 16.00 16.00 16.00 16.00 16.00 16.00 Total 100.00100.10 100.10 95.00 95.10 95.00 98.24 95.24 (base)/(sorbic acid) 1.450.50 0.50 0.65 0.79 1.07 1.45 1.29 (sorbic acid)/(tizanidine) 2.00 2.002.00 2.00 2.00 2.00 2.00 1.99 Cumulative skin permeation 166.50 137.00147.00 114.00 116.00 125.00 126.00 135.00 amount after 8 hr (μg/cm²)

All adhesive patches of Examples 4-1 to 4-8 exhibited excellenttransdermal permeability. It is considered because they contain sorbicacid, and ratio of sorbic acid to the medicament and ratio of basiccomponent to sorbic acid are both appropriate.

Example 5

Adhesive patches containing the composition (weight %) shown in Table 4were prepared. In vitro transdermal permeability test with use of pigskin was conducted for the obtained patches. The results are shown inTable 4.

TABLE 4 Ex. Ex. Ex. Ex. Ex. Ex. Ex. 5-1 5-2 5-3 5-4 5-5 5-6 5-7 T651T695 T697 T700 T702 T696 T739 Tizanidine Hydrochloride 1.72 1.72 1.721.72 1.72 1.72 1.72 Sorbic Acid 0.66 Potassium sorbate 0.89 0.89 0.890.89 0.89 0.89 0.89 Oleic acid 1.50 1.50 1.50 1.50 1.50 1.50Triethanolamine 0.5 0.5 0.4 Oleyl alcohol 10.00 10.00 10.00 10.00 10.0010.00 10.00 Myristyl alcohol 3.0 3.0 3.0 3.0 Glycerin 5.00 5.00 5.005.00 5.00 5.00 Concentrated glycerin 5.00 Purified water 0.50 Propyleneglycol 4.00 4.00 4.00 4.00 4.00 4.00 8.00 Butylene glycol 3.00 3.00 3.003.00 3.00 3.00 3.00 Medium-chain triglyceride 5.0 AEROSIL  ® 3 3 3 3 3 33 Liquid paraffin 18.08 23.24 23.34 26.74 23.74 23.74 22.24 Terpeneresin 32.00 28.00 28.00 28.00 28.00 28.00 28 SIS5002 16.00 16.00 16.0016.00 16.00 16.00 16 Sodium sulfite 0.10 0.10 0.10 0.10 0.10 0.10 Sodiumpyrosulfite 0.10 0.10 0.10 0.10 0.10 0.10 Propyl gallate 0.05 0.05 0.050.05 0.05 0.05 0.05 Total 100 100 100 100 100 100 100 (base)/(sorbicacid) 0.83 1.70 1.59 1.13 1.13 1.13 1.13 (Sorbatecomponent)/(tizanidine) 1.99 1.00 1.00 1.00 1.00 1.00 1.00 (aliphaticacid)/(base) 1.20 1.12 1.20 1.67 1.67 1.67 1.67 Cumulative skin) 4 hr0.4 2.1 1.9 3.6 0.8 2.4 3.5 permeation 6 hr 1.6 5.8 5.7 7.0 2.7 8.5 8.1amount 8 hr 4.5 10.5 11.0 12.0 6.1 17.7 14.6 (μg/cm²) 22 hr  84.0 51.254.5 98.7 57.8 105.2 91.9 24 hr  98.5 56.1 58.9 77.3 66.4 112.5 103.3

When potassium sorbate was used as sorbate component, excellenttransdermal permeability was observed in common with when sorbic acidwas used.

Example 6

Adhesive patches containing the composition (weight %) shown in Table 5were prepared. In vitro transdermal permeability test with use of pigskin was conducted for the obtained patches. The results are shown inTable 5.

TABLE 5 Ex. Ex. Ex. Ex. Com. Com. Com. Com. 6-1 6-2 6-3 6-4 6-1 6-2 6-36-4 M304 M306 M305 M307 M291 M295 M300 M303 Oxyco. HCl 3H₂O 3.461 3.4613.461 3.461 3.461 3.461 3.461 3.461 Sorbic Acid 0.7 0.7 Potassiumsorbate 1.3 1.3 1.3 1.3 Diisopropanolamine 1.5 1.5 1.5 1.5 1.5 1.5 1.5Triethanolamine 2.1 Potassium hydroxide 0.55 0.56 0.55 0.55 Levulinicacid 0.8 1.0 1.0 1.0 1.5 Oleic acid 3.0 3.0 3.0 3.0 4.0 4.0 4.0 4.0Myristic acid 5.0 Oleyl alcohol 10.0 10.0 10.0 10.0 3.0 10.0 10.0 10.0PEG200 5.0 Propylene carbonate 5.0 5.0 5.0 5.0 3.0 4.0 5.0 5.0 Glycerin5.00 5.00 5.00 5.00 5.00 5.00 Medium-chain triglyceride 10.0 10.0 10.010.0 10.0 10.0 100 Diethyl sebacate 5.0 Liquid paraffin 16.91 16.9117.61 16.81 18.34 17.73 17.34 16.84 AEROSIL ® 3.0 3.0 3.0 3.0 3.0 3.03.0 3.0 PX-1150N 26.0 26.0 26.0 26.0 27.0 26.0 26.0 26.0 SIS5002 15.015.0 15.0 15.0 15.0 15.0 15.0 15.0 Sodium pyrosulfite 0.1 0.1 0.1 0.10.1 0.1 0.1 0.1 Sodium sulfite Propyl gallate 0.05 0.05 0.05 0.05 0.050.05 0.05 0.05 Total 100 100 100 100 100 100 100 100 (base)/(sorbatecomponent) 1.38 1.38 2.38 2.38 (Sorbic acid)/(oxycodone) 1.73 1.73 1.001.00 0.00 0.00 0.00 0.00 (aliphatic acid)(base) 1.25 2.33 0.94 1.28 1.050.93 1.05 1.25 Cumulative skin 2 hr 0.881 0.858 0.675 1.000 1.561 0.08permeation 4 hr 10.39 6.52 11.23 0.997 11.22 14.28 0.491 6.088 amount 6hr 33.39 22.43 41.75 15.8 27.51 33.3 1.789 20.36 (μg/cm²) 8 hr 68.1245.37 73.08 33.5 47.66 62.07 4.059 39.98 24 hr  348.5 316.5 318.2 224.4183.5 186.8 40.22 182.1

All adhesive patches of Examples 6-1 to 6-4 containing sorbic acidexhibit excellent skin permeability.

INDUSTRIAL APPLICABILITY

The percutaneous absorption composition of the present disclosure can beused as adhesive patches containing basic medicament such as tizanidineor oxycodone.

What is claimed is:
 1. A percutaneous absorption non-aqueous compositioncomprising a basic medicament or a salt thereof and a sorbate component,wherein the molar ratio of the sorbic component to the basic medicamentor a salt thereof is 0.5-2.5.
 2. The percutaneous absorption compositionaccording to claim 1, wherein the sorbic component comprises a sorbicacid and/or a metal sorbate.
 3. The percutaneous absorption compositionaccording to claim 1, wherein the molar ratio of the sorbate componentto the basic medicament or a salt thereof is 0.5-2.5.
 4. Thepercutaneous absorption composition according to claim 1, furthercomprising a basic component.
 5. The percutaneous absorption compositionaccording to claim 4, wherein the basic component comprises one or moreof an organic basic component, an inorganic basic component, and a saltof a strong base.
 6. The percutaneous absorption composition accordingto claim 5, wherein the organic basic compound is a C₂₋₉ alkanolamine.7. The percutaneous absorption composition according to claim 5, whereinthe inorganic basic compound is a compound containing an alkali metal oran alkali earth metal.
 8. The percutaneous absorption compositionaccording to claim 4, wherein the molar ratio of the basic component tothe sorbate component is 0.4-3.0.
 9. A method for increase percutaneousabsorption of a basic medicament or a salt thereof comprising adding asorbic acid and/or a metal sorbate to a non-aqueous compositioncomprising the basic medicament or a salt thereof.
 10. The methodaccording to claim 9, wherein the molar ratio of the sorbic acid and/orthe metal sorbate to the basic medicament or a salt thereof is 0.5-2.5.11. The method according to claim 9 further comprising adding a basiccomponent to the non-aqueous composition.
 12. The method according toclaim 9, the molar ratio of the basic component to the to the sorbicacid and/or the metal sorbate is 0.4-3.0.
 13. The method according toclaim 9, wherein the basic component comprises at least one of anorganic basic component, an inorganic basic component, and a salt of astrong base.